Platelets may respond to a stimulus in the following progressive series of reactions: shape change, aggregation and granule secretion and arachiodonate oxidation. Substances in dense granules (ADP and 5-HT) and formed from arachidonate (Thromboxanes/prostaglandins) will activate platelets. Platelets can, therefore, be activated directly by the stimulus and, as a consequence of secretion and arachidonate oxidation, the strength of the stimulus is enhanced. Strong stimuli can activate platelets independent of the secretory and arachidonate pathways. The contribution of each pathway in platelet activation depends upon the amount of substance secreted or formed and the sensitivity of platelets to these substances. A comparative study of platelets is in progress to determine the former. This proposal will focus on the latter and will use platelets from domestic animals, laboratory animals, and man and animals with the Chediak-Higashi (CH) Syndrome. Animals with the CH syndrome offer the unique opportunity to study platelets which are devoid of ADP and 5-HT. Furthermore, we propose to examine the arachidonate pathway of domestic animals. Two recent developments have provided impetus for these studies. First, it was found that 5-HT induces a biphasic aggregation response in CH cat platelet which is inhibited by 5-HT antagonists and indomethacin. Furthermore, serotonin will induce thromboxane formation and arachidonate will irreversibly aggregate CH cat platelets. Second, we found that platelets from a certain breed of dogs will aggregate in response to arachidonate. These two findings offer the ability to study mechanisms by which platelets respond to arachidonate.